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EFFECTS OF PRENATAL TESTOSTERONE PROPIONATE ON SEXUAL DEVELOPMENT OF MALE AND FEMALE RATS: A DOSE-RESPONSE STUDY
Citation:
Wolf, C J., J S. Ostby, A. Hotchkiss, G. A. LeBlanc, AND L. E. Gray Jr. EFFECTS OF PRENATAL TESTOSTERONE PROPIONATE ON SEXUAL DEVELOPMENT OF MALE AND FEMALE RATS: A DOSE-RESPONSE STUDY. Presented at Society of Toxicology, San Francisco, CA, March 25 - 29, 2001.
Description:
Effects of Prenatal Testosterone Propionate on Sexual Development of Male and Female Rats: A Dose-Response Study
Cynthia Wolf1,2, Joe Ostby1*, Andrew Hotchkiss3, Gerald LeBlanc2, and L. Earl Gray, Jr.1
1USEPA, NHEERL, Reproductive Toxicology Division, RTP, NC; 2Dept. of Toxicology, NCSU, Raleigh, NC; 3USEPA/NCSU Cooperative Training Program, Raleigh, NC
Exposure of females to testosterone in utero can induce male sex characteristics such as increased anogenital distance (AGD), absence of nipples, and retention of Wolffian duct structures. However, high levels of androgens during fetal development can lead to toxic effects such as reduced litter size and viability. The study of the effects of testosterone in vivo provides a model for the identification of environmental androgens. In the current study, we investigate the ability of a range of concentrations of testosterone propionate (TP) to masculinize females without compromising number of offspring. Pregnant Sprague-Dawley rats were dosed on gestational day (GD) 14 - 19 (GD 1= day of plug) with 0.1 ml corn oil/rat sc or with TP at 0.1, 0.5, 1, 2, 5, or 10 mg/0.1 ml/rat. Maternal weight gain was reduced and parturition was delayed at 2, 5 and 10 mg TP. Litter size was reduced at 5 and 10 mg TP. AGD was measured on postnatal day (PND) 2. At 0.5 mg TP, AGD was reduced in the males but was not affected in the females. At 1 mg TP and above, female AGD had been increased and male AGD had been further decreased so that females and males had a "unisex" AGD. On PND 15 the number of areolas per female was significantly reduced by 0.5 mg TP. At weaning (PND 22), AGD remained significantly increased in the females at 1 mg TP and above. Females in these dose groups lacked a vaginal orifice. After puberty, many females in the 1, 2 and 5 mg TP dose groups developed a fluid-filled, distended uterus, graphically depicted by an inverted U-shaped dose-response. Most of these died soon thereafter. Necropsy of female offspring revealed a reduced number of nipples at 0.5 mg TP and virtually none by 1 mg TP; ventral prostate tissue in > 50% of the females at 0.5 mg TP; ventral prostate, levator ani and bulbourethral glands in females at 1 mg TP; and included seminal vesicle tissue at 2, 5 and 10 mg TP. We conclude that administration of 0.5 and 1 mg TP during organogenesis masculinizes female offspring without greatly affecting litter size or pregnancy of the dam. This abstract does not necessarily reflect USEPA policy.